Ether-containing inhibitors of 5-lipoxygenase

ABSTRACT

Compounds of the structure ##STR1## where Ar is optionally substituted carbocyclic aryl, 5- or 6-membered heterocyclic aryl, 10-membered bicyclic heterocyclic aryl containing one or two nitrogen atoms, 9- or 10-membered heterocyclic containing one or two nitrogen atoms and optionally containing a further nitrogen or oxygen atom and one oxo or thioxo substituent, benzo[b]furyl, or benzo[b]thienyl, A 1  is propynyl, methylene, or a direct link to X, X is oxy, thio, sulfonyl, or NR 4 , A 2  is selected from ##STR2## where Y is hydrogen, halogen, or nitrile; Z is hydrogen, R 1  is alkyl, and R 2  is hydrogen or alkyl are potent inhibitors of lipoxygenase enzymes and thus inhibit the biosynthesis of leukotrienes. These compounds are useful in the treatment or amelioration of allergic and inflammatory disease states.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of co-pending application Ser. No.07/935,079 filed Aug. 24, 1992, now U.S. Pat. No. 5,268,379.

TECHNICAL FIELD

This invention relates to compounds having biological activity toinhibit lipoxygenase enzymes, to pharmaceutical compositions comprisingthese compounds, and to a medical method of treatment. Moreparticularly, this invention concerns certain ether-containing compoundswhich inhibit leukotriene biosynthesis, to pharmaceutical compositionscomprising these compounds and to a method of inhibiting lipoxygenaseactivity and leukotriene biosynthesis.

BACKGROUND OF THE INVENTION

5-Lipoxygenase is the first dedicated enzyme in the pathway leading tothe biosynthesis of leukotrienes. This important enzyme has a ratherrestricted distribution, being found predominantly in leukocytes andmast cells of most mammals. Normally 5-lipoxygenase is present in thecell in an inactive form; however, when leukocytes respond to externalstimuli, intracellular 5-lipoxygenase can be rapidly activated. Thisenzyme catalyzes the addition of molecular oxygen to fatty acids withcis, cis-1,4-pentadiene structures, converting them to1-hydroperoxytrans, cis-2,4-pentadienes. Arachidonic acid, the5-lipoxygenase substrate which leads to leukotriene products, is foundin very low concentrations in mammalian cells and must first behydrolyzed from membrane phospholipids through the actions ofphospholipases in response to extracellular stimuli. The initial productof 5-lipoxygenase action on arachidonate is 5-HPETE which can be reducedto 5-HETE or converted to LTA₄. This reactive leukotriene intermediateis enzymatically hydrated to LTB₄ or conjugated to the tripeprideglutathione to produce LTC₄. LTA₄ can also be hydrolyzednonenzymatically to form two isomers of LTB₄. Successive proteolyticcleavage steps convert LTC₄ to LTD₄ and LTE₄. Other products resultingfrom further oxygenation steps have also been described in theliterature. Products of the 5-lipoxygenase cascade are extremely potentsubstances which produce a wide variety of biological effects, often inthe nanomolar to picomolar concentration range.

The remarkable potencies and diversity of actions of products of the5-lipoxygenase pathway have led to the suggestion that they playimportant roles in a variety of diseases. Alterations in leukotrienemetabolism have been demonstrated in a number of disease statesincluding asthma, allergic rhinitis, rheumatoid arthritis and gout,psoriasis, adult respiratory distress syndrome, inflammatory boweldisease, endotoxin shock syndrome, atherosclerosis, ischemia inducedmyocardial injury, and central nervous system pathology resulting fromthe formation of leukotrienes following stroke or subarachnoidhemorrhage.

The enzyme 5-lipoxygenase catalyzes the first step leading to thebiosynthesis of all the leukotrienes and therefore inhibition of thisenzyme provides an approach to limit the effects of all the products ofthis pathway. Compounds which inhibit 5-lipoxygenase are thus useful inthe treatment of disease states such as those listed above in which theleukotrienes play an important role.

SUMMARY OF THE INVENTION

In its principal embodiment, the present invention provides certaintriether compounds which inhibit lipoxygenase enzyme activity and areuseful in the treatment of allergic and inflammatory disease states inwhich leukotrienes play a role.

The compounds of this invention have the structure ##STR3## wherein Aris selected from the group consisting of

(a) carbocyclic aryl, optionally substituted with alkyl of from one tosix carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy offrom one to six carbon atoms, or halogen,

(b) 5- or 6-membered heterocyclic aryl, optionally substituted withalkyl of from one to six carbon atoms, haloalkyl of from one to sixcarbon atoms, alkoxy of from one to six carbon atoms, or halogen,

(c) 10-membered bicyclic heterocyclic aryl containing one or twonitrogen atoms, optionally substituted with alkyl of from one to sixcarbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of fromone to six carbon atoms, or halogen,

(d) benzo[b]furyl, optionally substituted with alkyl of from one to sixcarbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of fromone to six carbon atoms, or halogen,

(e) benzo[b]thienyl, optionally substituted with alkyl of from one tosix carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy offrom one to six carbon atoms, or halogen, ##STR4## wherein R₃ and R₄ areindependently hydrogen or alkyl of from one to four carbon atoms.

A₁ is propynyl, methylene, or a direct link to X.

X is oxy, thio, sulfonyl, or NR₄, wherein R₄ is as defined above, and A₂is selected from the group consisting of ##STR5## R₃ is as definedabove; Y is hydrogen, halogen, or nitrile, and Z is hydrogen or alkyl offrom one to four carbon atoms, with the proviso that when X is NH, A₂ is##STR6##

The group R₁ is alkyl of from one to four carbon atoms, and R₂ ishydrogen or alkyl of from one to four carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms

As used throughout this specification and the appended claims, the term"alkyl" refers to a monovalent group derived from a straight or branchedchain saturated hydrocarbon by the removal of a single hydrogen atom.Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-,sec-, iso- and tert-butyl, and the like.

The term "carbocyclic aryl" denotes a monovalent carbocyclic ring groupderived by the removal of a single hydrogen atom from a monocyclic orbicyclic fused or non-fused ring system obeying the "4n+2π electron" orHuckel aromaticity rule. Examples of carbocyclic aryl groups includephenyl, 1-, and 2-naphthyl, biphenyl and the like.

The term "5- or 6-membered heterocyclic aryl" denotes a monovalentheterocyclic ring group derived by the removal of a single hydrogen atomfrom a monocyclic heterocyclic ring system obeying the "4n+2π electron"or Huckel aromaticity rule. Examples of 5, or 6-membered heterocyclicaryl groups include pyridinyl, furyl, thienyl, thiazolyl, imidazolyl,and pyrimidinyl.

The term "10-membered bicyclic heterocyclic aryl containing one or twonitrogen atoms" refers to a group selected from quinolinyl,isoquinolinyl, quinazolinyl, phthalazinyl, and quinoxalinyl.

The term "9- or 10-membered heterocyclic aryl containing one or twonitrogen and optionally containing a further heteroatom selected fromnitrogen or oxygen, and one oxo or thioxo substituent" refers to a groupselected from 2-oxo-1,2-dihydroquinolinyl,2-oxo-1,2,3,4-tetrahydroquinolinyl,3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl, oxindolinyl, 3-oxo-1,2-dihydro-3H-indazolyl, 2-oxo-2,3-dihydrobenzothiazolyl,2-oxo-2,3-dihydrobenzimidazolyl,3-thioxo-2,3-dihydro-4H-1,4-benzoxazinyl, and 2-thioxo-1,2,3,4-tetrahydroquionlinyl.

The term "oxo" denotes a carbonyl oxygen atom.

The term "thioxo" denotes an oxo group as defined above in which theoxygen atom is replaced by a sulfur atom.

The term "propynyl" refers to a straight chain, three-carbon groupcontaining a carbon-carbon triple bond.

The texan "hydroxyalkyl" represents an alkyl group, as defined above,substituted by one to three hydroxyl groups with the proviso that nomore than one hydroxy group may be attached to a single carbon atom ofthe alkyl group.

The term "haloalkyl" denotes an alkyl group, as defined above, havingone, two, or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifiuoromethyl, and the like.

The terms "alkoxy" and "alkoxyl" denote an alkyl group, as definedabove, attached to the parent molecular moiety through an oxygen atom.Representative alkoxy groups include methoxyl, ethoxyl, propoxyl,butoxyl, and the like.

The term "alkenyl" denotes a monovalent group derived from a hydrocarboncontaining at least one carbon-carbon double bond by the removal of asingle hydrogen atom. Alkenyl groups include, for example, ethenyl,propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.

The term "alkylene" denotes a divalent group derived from a straight orbranched chain saturated hydrocarbon by the removal of two hydrogenatoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene,2,2-dimethylpropylene, and the like.

The term "alkenylene" denotes a divalent group derived from a straightor branched chain hydrocarbon containing at least one carbon-carbondouble bond. Examples of alkenylene include --CH═CH--, --CH₂ CH═CH--,--C(CH₃)═CH--, --CH₂ CH═CHCH₂ --, and the like.

Compounds contemplated as falling within the scope of the presentinvention include, but are not limited to:

4-methoxy-4-[3-((napth-2-yl)methoxy)-prop- 1 -ynyl]tetrahydropyran;

4-methoxy-4-[3-methyl-3-(((napth-2yl)methoxy))-prop- 1-ynyl]tetrahydropyran;

4-methoxy-4-[3- ((napth-2yl)methoxy)-trans-prop-1-enyl]tetrahydropyran;

4-methoxy-4-[3-methyl-3-((napth-2yl)methoxy)-trans-prop-1-enyl]tetrahydropyran;

4-methoxy-4-[3-((napth-2yl)methoxy)propyl]tetrahydropyran;

4-methoxy-4-[3-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy)-trans-prop-1-enyl]tetrahydropyran;

4-methoxy-4-[3-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy)-trans-prop-1-enyl]-2-methyltetrahydropyran;

4-methoxy-4-[3-((4-phenylphen-1-yl)methoxy)-trans-prop-1-enyl]tetrahydropyran;

4-methoxy-4-[3 -(napth-2-ylthioxy)-trans-prop-1-enyl]tetrahydropyran;

3-(4-methoxytetrahydropyran-4-yl)-N-((napth-2-yl)methyl)-trans-propionylamide;

3-(4-methoxytetrahydropyran-4-yl)-N-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methyl)-trans-propionylamide; and

4-methoxy-4-[3-((2-(pyrid-2-yl)ethynyl)methoxy)-trans-prop-1-enyl]tetrahydropyran.

Preferred compounds are those in which Ar is selected from the groupconsisting of ##STR7##

Particularly preferred compounds of the present invention are:

4-methoxy-4-[3-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy)-trans-prop-1-enyl]tetrahydropyran;and

3-(4-methoxytetrahydropyran-4-yl)-N-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methyl)-trans-propionylamide.

Lipoxygenase Inhibition Determination

Inhibition of leukotriene biosynthesis was evaluated in an assay,involving calcium ionophore-induced LTB₄ biosynthesis expressed humanwhole blood. Human heparinized whole blood was preincubated with testcompounds or vehicle for 15 min at 37° C. followed by calcium ionophoreA23187 challenge (final concentration of 8.3 μM) and the reactionterminated after 30 min by adding two volumes of methanol containingprostaglandin B₂ as an internal recovery standard. The methanol extractwas analyzed for LTB₄ using a commercially available radioimmunoassay.

The compounds of this invention inhibit leukotriene biosynthesis asillustrated in Table 1.

                  TABLE 1                                                         ______________________________________                                        In Vitro Inhibitory Potencies of Compounds of                                 this Invention Against 5-Lipoxygenase from Stimulated                         LTB.sub.4 Formation in Human Whole Blood                                      Example            IC.sub.50 (10.sup.-6 M)                                    ______________________________________                                        1                  3.8                                                        2                  95% at 12.5 μM                                          3                  0.70                                                       4                  99% at 12.5 μM                                          5                  1.5                                                        6                  51% at 0.39 μM                                          8                  11% at 12.5 μM                                          19                 34% at 0.10 μM                                          20                 0.26                                                       21                 50% at 0.39 μM                                          22                 18% at 12.5 μM                                          ______________________________________                                    

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.The term "parenteral" administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intrapexitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such ms lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonitc clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as failers insoft and hard-failed gelatin capsules using such excipients as lactoseor mill sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonitc, agaragar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable nonirritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any nontoxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be Used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers, or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about5 to about 20 mg of active compound per kilogram of body weight per dayare administered orally to a mammalian patient. If desired, theeffective daily dose may be divided into multiple doses for purposes ofadministration, e.g. two to four separate doses per day.

Preparation of the Compounds of this Invention

In general, the compounds of this invention are synthesized by reactionschemes I-IV as illustrated below. It should be understood that Ar, R,R₁ and R₂ as used herein correspond to the groups identified by formulaI. ##STR8##

According to the foregoing reaction Scheme I, the magnesium salt ofO-THP propargyl alcohol is condensed with the suitably substitutedtetrahydropyran-4-one to give tertiary alcohol I. The alkynyl compoundIV is prepared by alkylation of alcohol I by treatment with base,preferably sodium hydride and the desired alkyl halide. The THPprotecting group is then removed, preferably bu pyridiniump-toluenesulfonate in methanol, and the resulting alcohol III isalkylated by treatment with base, preferably sodium hydride and thedesired arylmethyl bromide to give IV.

The alkenyl compound VIII is prepared by reduction of alkyne I to thetrans olefin V with a suitable reducing agent, preferably Red-Al (sodiumbis(2-methoxyethoxy)aluminum). V is then converted to VIII byalkylation, deprotection, and alkylation as described for thepreparation of IV. Most preferably, the alkenyl compound VIII isprepared by reduction of acetylene III to the trans-olefin VII withRed-Al; subsequent alkylation, as described above, provides VIII.

Hydrogenation of either IV or VIII, preferably cayalyzed with palladiumon barium carbonate poisoned with lead gives saturated compound IV.##STR9##

According to the foregoing reaction Scheme II, the hydroxyl group inalcohol VII is converted to suitable leaving group, preferably themesylate. The mesylate is then converted to the iodide XI, preferably bytreatment with sodium iodide. The iodide is then displaced with thedesired aryl thiolate, prepared by treatment of the corresponding arylthiol with base, preferably sodium hydride. Arylmethyl compound XIII isprepared according to the method of compound XII, except arylmethylthiol is substituted for aryl thiol. ##STR10##

According to the foregoing reaction Scheme III, primary alcohol XIV isoxidized to carboxylic acid XV by treatment with a suitable oxidizingagent, preferably Jones Reagent. The carboxylic acid is converted to theacid chloride XVI, preferably by treatment with oxalyl chloride. AmideXVII is prepared by treatment of the acid chloride with the desiredarymethylamine in the presence of a suitable base, preferablytriethylamine. ##STR11##

According to the foregoing reaction Scheme IV, the requisitetetrahydro-4H-pyran-4-one is treated with vinylmagnesium bromide and theresulting alcohol is alkylated by treatment with base, preferably sodiumhydride and the desired alkyl halide to give XIX. Aldehyde XX isprepared by treatment of XIX with ozone and decomposition of theresulting ozonide, preferably with dimethyl sulfide. Trans olefin XXI isprepared by treatment of aidehyde XX with the ylide resulting fromtreatment of triethyl phosphonofluoroacetate with base, preferablytert-butyllithium. XXI is converted to acid chloride XXII bysaponification with lithium hydroxide and treatment with oxalylchloride, or to alcohol XXIII by reduction with a suitable reducingagent, preferably sodium borohydride in the presence of cerium (III)chloride.

The foregoing may be better understood from the following Examples,which are presented for the purpose of illustration and not intended tolimit the scope of the inventive concept.

EXAMPLE 1 Preparation of 4-methoxy-4-[3-((napth-2-yl)methoxy)-prop-1-ynyl]tetrahydropyran Step 1:4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran

Tetrahydro-2-(2-propynyloxy)-2H-pyran (21 g, 150 mmol) was converted tothe corresponding magnesium anion by deprotonation with ethyl magnesiumbromide (75 mL of a 2M solution, 150 mmol) according to the methoddescribed in Org. Synth., 60:81-7 (1981). The resulting anion was cooledto -20 ° C. and tetrahydro-4H-pyran-4-one (14.8 g, 148 mmol) in dry THF(30 mL) was added dropwise and the resulting solution stirred for threehours. The reaction was quenched by addition of crushed ice andsaturated aqueous ammonium chloride. The resulting two-layered mixturewas extracted with ether (3×150 mL). The combined organic layers weredried (MgSO₄), filtered, and concentrated in vacuo. Purification bychromatography on silica gel (200 g, 20% ethyl acetate: hexanes)provided the desired acetylene tertiary alcohol (31.4 g, 88%).

Step 2:4-methoxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran

To a suspension of sodium hydride (1.2 g of an 80% oil dispersion, 50mmol) in dry THF (45 mL) was added a solution of4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran(3.71 g, 15.3 mmol), prepared as in step 1. After hydrogen evolutionceased, methyl iodide (3.0 mL, 48.2 mmol) was added neat and theresulting solution was stirred overnight at ambient temperature. Thereaction was quenched by addition of crushed ice and saturated aqueousammonium chloride. The resulting two-phase mixture was extracted withether (3×100 mL). The combined organic layers were dried (MgSO₄),filtered, and concentrated in vacuo. Purification by chromatography onsilica gel (100 g, 10% ethyl acetate: hexanes) provided the methyl ether(3.74 g, 95%) as a colorless oil.

Step 3: 4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran

To a solution of4-methoxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran(3.8 g, 14.8 mmol), prepared as in step 2, in methanol (50 mL), wasadded a catalytic mount of pyridinium p-toluenesulfonate (PPTS). Theresulting yellow solution was stirred under nitrogen for 17 hours atambient temperature. The volatiles were removed in vacuo and the residuewas dissolved in ethyl acetate and treated with saturated aqueousammonium chloride. The organic layer was dried (MgSO4), filtered, andconcentrated in vacuo. Purification by chromatography on silica gel (100g, 30% ethyl acetate: hexanes)provided the primary alcohol (1.2 g, 47%)as a colorless oil.

Step 4: 4-methoxy-4-[3-((napth-2-yl)methoxy)-prop-1-ynyl]tetrahydropyran

4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran (1.2 g, 6.97 mmol) wastreated with sodium hydride in THF (18 mL). After gas evolution ceased,a solution of 2-(bromomethyl)napthalene (1.70 g, 7.67 mmol) in dry DMF(9 mL) was added. After 3 hours at ambient temperature the reaction wasquenched with saturated aqueous ammonium chloride. The resultingtwo-phase mixture was extracted with ether (3×100 mL). The combinedorganic layers were dried (MgSO4), filtered, and concentrated in vacuo.Purification by chromatography on silica gel (100 g, 10% ethyl acetate:hexanes) provided the title compound. (2.00 g, 92%) as a colorless oil.¹ H NMR (300 MHz, CDCl₃); 7.80-7.90 (4H, m), 7.47-7.52 (3H, m), 4.70(2H, s), 4.32 (2H, s), 3.87 (2H, dd, J=12,4.5 Hz), 3.67 (2H, dd, J=12,3Hz), 3.40 (3H, s), 1.95 (2H, br d, J=13 Hz), 1.49 (2H, ddd, J=13,9,4.5Hz); MS (M+NH₄)⁺ =328. Analysis calc'd for C₂₀ H₂₂ O₃ : C, 77.39; H,7.14; Found: C, 76.10; H, 7.10.

EXAMPLE 2 Preparation of4-methoxy-4-[3-methyl-3-(((napth-2yl)methoxy))-prop-1-ynyl]tetrahydropyran

The desired compound was prepared according to the method of Example 1except substituting tetrahydro-2-(1-methyl-2-propynyloxy)-2H-pyran fortetrahydro-2-(2-propynyloxy)-2H-pyran.4-methoxy-4-[3-methyl-3-(((napth-2yl)methoxy))-prop-1-ynyl]tetrahydropyranwas isolated as a clear oil. ¹ H NMR (300 MHz, CDCl₃); 7.80-7.87 (4H,m), 7.47-7.51 (3H, m), 4.93 (1H, AB, J=12 Hz), 4.69 (1H, AB, J=12 Hz),4.34 (1H, q, J=6.5 Hz), 3.88 (2H, dt, J=12,4.5,4.5 Hz), 3.67 (2H, ddt,J=11.5,9.5,3,3 Hz), 3.40 (3H, s), 1.95 (2H, br d, J=13.5 Hz), 1.49 (2H,ddd, J=13.5,9,4.5 Hz); MS (M+NH₄)⁺ =342. Analysis calc'd for C₂₁ H₂₄ O₃: C, 77.75; H, 7.46; Found: C, 77.50; H, 7.38.

EXAMPLE 3 Preparation of4-methoxy-4-[3-((napth-2yl)methoxy-trans-prop-1-enyl]tetrahydropyranStep 1:4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-trans-prop-1-enyl]tetrahydropyran

A solution of4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1ynyl]tetrahydropyran(10.8 g, 44.9 mmol), prepared as in Example 1, step 1, in dry THF (100mL) was cooled to -75 ° C., and Red-Al (20 mL of 3.4M solution intoluene, 68 mmol) was added under a dry argon atmosphere. The coolingbath was removed and the reaction was warmed to 0° C. and quenched byaddition of crashed ice and saturated aqueous ammonium chloride. Theresulting two-phase mixture was extracted with ethyl acetate (4×90 mL).The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. Purification by chromatography on silica gel (100g, 10% ethyl acetate: hexanes) provided the trans-olefin (3.71 g, 34 %)as a colorless oil.

Step 2:4-methoxy-4-[3-((napth-2yl)methoxy)-trans-prop-1-ene]tetrahydropyran

The desired compound was prepared according to the method of Example I,steps 2-4 except substituting4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-trans-prop-1enyl]tetrahydropyran,prepared as in step 1, for4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran.Purification by chromatography on silica gel afforded4-methoxy-4-[3-((napth-2yl)methoxy)-trans-prop-1-ene]tetrahydropyran asa colorless oil. ¹ H NMR (300 MHz, CDCl₃); 7.78-7.86 (4H, m), 7.47-7.52(3H, m), 5.77 (1H, dt, J=16,5 Hz), 5.63 (1H, dt, J=16,1 Hz), 4.70 (2H,s), 4.12 (2 H, dd, J=5,1 Hz), 3.67-3.8 (4H, m), 3.15 (3H, s), 1.72-1.77(4H, m); Analysis calc'd for C₂₀ H₂₄ O_(3:) C, 76.89; H, 7.74; Found: C,76.70; H, 7.71. MS (M+H)⁺ =330, (M+NH₄)⁺ =347.

EXAMPLE 4 Preparation of 4-methoxy-4-[3-methyl-3-((napth-2yl)methoxy)-trans-prop-1-enyl]tetrahydropyran

The desired compound was prepared as a colorless oil according to themethod of Example 3, except substituting4-hydroxy-4-[3-methyl-3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran,prepared as in Example 2, for4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran. ¹H NMR (300 MHz, CDCl₃); 7.75-7.85 (4H, m), 7.43-7.5 (3H, m), 5.62 (1H,dd, J=13,6 Hz), 5.53 (1H, d, J=13 Hz), 4.02 (1H, pentet, J=6 Hz),3.65-3.82 (4H, m), 3.17 (3H, 1.72-1.80 (4H, m), 1.33 (3H, d, J=6 Hz);(M+NH₄)⁺ =344. Analysis calc'd for C₂₁ H₂₆ O₃ : C, 77.27; H, 8.03;Found: C, 77.00; H, 7.82.

EXAMPLE 5 Preparation of 4-methoxy-4-[3-((napth-2yl)methoxy)-prop-1-yl]tetrahydropyran

4-methoxy-4-[3-methyl-3-((napth-2yl)methoxy)-trans-prop-1-enyl]tetrahydropyran(320 mg, 1.02 mmol), prepared as in Example 3, was hydrogenated overpalladium on calcium carbonate, poisoned with lead, with hydrogen (1atm) in ethyl acetate at ambient temperature for 18 hours. Afterflushing the reaction solution with nitrogen, the solution was filteredthrough a pad of celite. The filter cake was thoroughly rinsed withethyl acetate. The combined flltrates were concentrated in vacuo andchromatographed on silica gel (14 g, 15% ethyl acetate:hexanes) toprovide the title compound (214 mg, 66%) as a colorless oil. ¹ H NMR(300 MHz, CDCl₃); 7.75-7.87 (4H, m), 7.43-7.53 (3H, m), 4.67 (2H, s),3.68 (4H, d,d, J=8,3 Hz), 3.52 (2H, t, J=6 Hz), 3.17 (3H, s), 1.49-1.78MS (M+H)⁺ =315, (M+NH₄ )⁺ =332. Analysis calc'd for C₂₀ H₂₆ O₃ : C,76.40; H, 8.33; Found: C, 76.30; H, 8.12.

EXAMPLE 6 Preparation of4-methoxy-4-[3-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy)-trans-prop-1-enyl]tetrahydropyran

The desired compound was prepared according to the method of Example 1,step 4, except substituting4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran, prepared as inExample 3, for 4-methoxy-4-(3-hydroxyprop-1 -ynyl)tetrahydropyran, andsubstituting 1,2-dihydro-1-methyl-2-oxo-6-(bromomethyl)quinoline for2-(bromomethyl)naphthalene. ¹ H NMR (300 MHz, CDCl₃); 7.67 (1H, d, J=9Hz), 7.52-7.58 (2H, m), 7.35 (1H, d, J=9 Hz), 6 (1H, d, J=9 Hz), 5.75(1H, dt, J=15.5,8 Hz), 5.63 (1H, br d, J=16 Hz), 4.60 (2H, s), 4.10 (2H,dd, J=8,1 Hz), 3.67-3.8 (4H, m), 3.15 (3H, s), 1.72-1.77 (4H, m); MS(M+H)⁺ =344. Analysis calc'd for C₂₀ H₂₅ NO₄ : C, 69.95; H, 7.34; N,4.08; Found: C, 69.68; H, 7.16; N, 3.99

EXAMPLE 7 Preparation of 4-methoxy-4-[3-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy-trans-prop-1-enyl]-2-methyltetrahydropyranStep 1:4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran

The desired compound was prepared according to the method of Example 1,step 1 except substituting 2-methyltetrahydro-4H-pyran-4-one fortetrahydro-4H-pyran-4-one.

Step 2:4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-trans-prop-1-enyl]-2-methyltetrahydropyran

The desired compound was prepared according to the method of Example 3,step 1, except substituting4-hydroxy-4-[3-tetrahydropyran-2-yloxy)-prop-1-ynyl]-2-methyltetrahydropyran,prepared as in step 1, for4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran.

Step 3:4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)-2-methyltetrahydropyran

The desired compound was prepared according to the method of Example 1,steps 2 and 3 except substituting4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-trans-prop-1-enyl]-2-methyltetrahydropyranfor 4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran.

Step 4;4-methoxy-4-[3-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy)-trans-prop-1-enyl]-2-methyltetrahydropyran

The desired compound was prepared according to the method of Example 6,except substituting4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)-2-methyltetrahydropyran for4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran

EXAMPLE 8 Preparation of4-methoxy-4-[3-((4-phenylphen-1-yl)methoxy)-trans-prop-1-enyl]tetrahydropyran

The desired compound was prepared according to the method of Example 3,except substituting 4-pheynylphen-1-ylmethyl bromide fornapth-2-ylmethyl bromide. Purification by chromatography on silica gel(16 g, 10% ethyl acetate: hexanes), provided4-methoxy-4-[3-((4-phenylphen-1-yl)methoxy)-trans-prop-1enyl]tetrahydropyran.(251 mg, 74%) as a colorless oil. ¹ H NMR (300 MHz, CDCl₃); 7.57-7.65(4H, m), 7.32-7.52 (5H, m), 5.78 (1H, dt, J=15.5, 5,5 Hz), 5.65 (1H, d,J=15.5 Hz), 4.60 (2H, s), 3.68-3.82 (4H, m), 3.18 (3H, s), 1.72-1.80(4H, m); MS (M+NH₄)⁺ =356. Analysis calc'd for C₂₂ H₂₆ O₃ : C, 78.07; H,7.74; Found: C, XXX; H, XXX.

The compounds represented in Table 2 are prepared by alkylation of theappropriate allylic alcohol, obtained as described in Examples 3 or 7with the requisite arylmethyl or heteroarylmethyl halide according tothe method of Example 1, step 4.

                  TABLE 2                                                         ______________________________________                                        Novel Aryl- and Heteroarylmethyloxy Substituted Olefin                        Triethers                                                                      ##STR12##                                                                    Example                                                                              R.sub.2                                                                              Ar                                                              ______________________________________                                         9     H                                                                      quionoxalin-6-yl                                                              10     CH.sub.3                                                               quionoxalin-6-yl                                                              11     H                                                                      quinolin-6-yl                                                                 12     CH.sub.3                                                               quinolin-6-yl                                                                 13     H      1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl                  14     CH.sub.3                                                                             1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl                  15     H      2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-                                     benzoxazin-7-yl                                                 16     CH.sub.3                                                                             2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-                                     benzoxazin-7-yl                                                 17     H      1,3-dimethyl-2-oxo-2,3-dihydrobenz-imidazol-5-yl                18     CH.sub.3                                                                             1,3-dimethyl-2-oxo-2,3-dihydrobenz-imidazol-5-yl                ______________________________________                                    

EXAMPLE 19 Preparation of4-methoxy-4-[3-(napth-2-ylthioxy)-trans-prop-1-enyl]tetrahydropyran Step1: 4-methoxy-4-(3-methanesulfonyl-trans-prop-1-enyl)tetrahydropyran

4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran, prepared as inExample 3, was converted to the corresponding mesylate according to themethod of Crossland and Servis, J. Org. Chem., 35, 3195-3196 (1970).

Step 2: Preparation of4-methoxy-4-(3-iodo-trans-prop-1-enyl)tetrahydropyran

To a 0° C. solution in acetone of4-methoxy-4-(3-methanesulfonyl-trans-prop-1-enyl)tetrahydropyran (505mg, 2.02 mmol), prepared as in step 1 was added sodium iodide (605 mg,4.03 mmol), and the reaction was stirred for 15 min. The reaction waspartitioned between ethyl acetate and brine. The organic layer waswashed (2×, brine), dried (MgSO₄), filtered and concentrated in vacuo toprovide the desired iodide (550 mg, 97%) as a dark yellow oil. Theiodide was of sufficient purity to use without further purification.

Step 3:4-methoxy-4-[3-(napth-2-ylthioxy)-trans-prop-1-enyl]tetrahydropyran

To a stirred solution of sodium hydride (186 mg, 60% dispersion inmineral oil, 4.66 mmol) in dry DMF (2 mL) was added napthyl-2-thiol (374mg, 2.33 mmol) in dry DMF (4 mL). After gas evolution ceased, the iodidefrom step 2 (990 mg, 3.50 mmol), was added in dry DMF (6 mL) and theresulting mixture was stirred 0.5 hours at ambient temperature. Thereaction was quenched by careful addition of saturated aqueous ammoniumchloride and partitioned between ethyl acetate and brine. The organiclayer was washed (1×, water; 2×, brine), dried (1MgSO₄), filtered, andconcentrated in vacuo. Purification by chromatography on silica gel (12g, 10% ethyl acetate: hexanes) afforded the title compound (606 mg, 83%)as a yellow oil. ¹ H NMR (300 MHz, CDCl₃); 7.71-7.80 (4H, m), 7.40-7.50(3H, m), 5.65 (1H,dt, J=15.5,7,7 Hz), 5.38 (1H, dt, J=15.5,1,1 Hz), 3.67(2H, dd, J=7.5,1 Hz), 3.50- 3.70 (4H, m), 2.88 (3H, s), 1.55-1.63 (4H,m); MS (M+H)⁺ =288. Analysis calc'd for C₁₉ H₂₂ O₂ S: C, 72.58; H, 7.05.Found: C, 72.30; H, 6.85.

EXAMPLE 20 Preparation of3-(4-methoxytetrahydropyran-4-yl)-N-((napth-2-yl)methyl)-trans-propionylamide Step 1: 3-(4-methoxytetrahydropyran-4-yl)-trans-propenoic acid

4-(3-hydroxy-trans-prop-1-enyl)-4-methoxy-tetrahydropyran (175 mg, 1.02mmol), prepared as in Example 1, steps 1-3, was oxidized to thecorresponding carboxylic acid by treatment with a slight excess of Jonesreagent in cold acetone.

Step 2: 3-(4-methoxytetrahydropyran-4-yl)-trans-propenoyl chloride

The acid chloride was prepared by treatment of3-(4-methoxytetrahydropyran-4-yl)-trans-propenoic acid (160 mg, 0.86mmol), prepared as in step 1, with oxalyl chloride.

Step 3:3-(4-methoxytetrahydropyran-4-yl)-N-((napth-2-yl)methyl)-trans-propionylamide

A solution of 3-(4-methoxytetrahydropyran-4-yl)-trans-propenoylchloride, 2-aminomethylnapthalene (141 mg, 0.90 mmol), and triethylamine(202 mg, 2.0 mmol) in dichloromethane (4 mL) was stirred at ambienttemperature for one hour. The reaction mixture was partitioned betweenethyl acetate and brine. The combined organic layers were dried (MgSO₄),filtered, and concentrated in vacuo. Purification by chromatography onsilica gel (16 g, 25% ethyl acetate: hexanes), provided the titlecompound (73 mg, 26%) as a colorless oil.. ¹ H NMR (300 MHz, CDCl₃);7.67-7.87 (4H, m), 7.52-7.58 (2H, m), 7.32-7.51 (3H, m), 6.81 (1H, d,J=15 Hz), 5.92 (1H, d, J=15 Hz), 5.87 (1H, br m), 4.70 (2H, d, J=6 Hz),3.70-3.77 (4H, m), 3.18 (3H, s), 1.72-1.80 (4H, m); MS (M+H)⁺=326,(M+NH₄)⁺ =343. Analysis calc'd for C₂₀ H₂₃ NO₃ : C, 73.82; H, 7.12;N, 4.30; Found: C, 73.70; H, 7.05; N, 4.20.

EXAMPLE 21 Preparation of3-(4-methoxytetrahydropyran-4-yl)-N-((1,2,-dihydro-1-methyl-2-oxoquinolin-6-yl)methyl)-trans-propionylamide Step 1: (1,2-dihydro-1-methyl-2-oxoquinoline-6-yl)methylamine

To a solution of 1,2-dihydro-1-methyl-2-oxo-6-(bromomethyl)quinoline(505 mg, 2.0 mmol) in dry THF (6 mL) was added in a dropwise fashion asolution of sodium azide (310 mg, 4.77 mmol) in 1:1 ethanol:water (7mL). The resulting solution was stirred for 4 hours and concentrated to˜1/2 of the original volume. The aqueous phase was extracted with ethylacetate (4×). The combined organic layers were dried (MgSO₄), filtered,and concentrated in vacuo to give the desired azide of sufficient purityto carry on without further purification. The azide (428 mg, 2.00 mmol)was reduced to the corresponding amine by exposure to propanedithiol(0.60 mL, 6.0 mmol) and triethylamine (0.84 mL, 6.0 mmol) in absoluteethanol (3 mL) and dry THF (4 mL) for seventeen hours at ambienttemperature. The reaction was filtered and the filter cake washed withTHF and ethyl acetate. The combined flitrates were dried (MgSO₄),filtered, and concentrated in vacuo to give the desired amine.Purification by silica gel chromatography (8 g, 50% ethylacetate:hexanes, then ethyl acetate, and then 70:20:10 ethylacetate:ethanol:THF) provided(1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methylamine.

Step 2;3-(4-methoxytetrahydropyran-4-yl)-N-((1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methyl)-trans-propionylamide

A solution of 3-(4-methoxytetrahydropyran-4-yl)-trans-propenoyl chloride(1.0 mmol) prepared according to the method of Example 20, steps 1 and2, (1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methylamine (188 mg, 1.00mmol), and triethylamine (303 mg, 3.0 mmol) in dichloromethane (5 mL)was stirred at ambient temperature for one hour. The reaction mixturewas partitioned between ethyl acetate and brine. The combined organiclayers were dried (MgSO₄), filtered, and concentrated in vacuo.Purification by chromatography on silica gel (16 g, 25% ethyl acetate:hexanes, then 40% ethyl acetate: hexanes), provided the title compound(1.58 g, 44%) as a colorless solid. mp 141°-143° C.; ¹ H NMR (300 MHz,CDCl₃); 7.61 (1H, d, J=9 Hz), 7.47-7.55 (2H, m), 7.31 (1H, d, J=9 Hz),6.81 (1H, d, J=15.5 Hz), 6.67 (1H, d, J=9 Hz), 6.13 (1H, br t, J=6 Hz),5.95 (1H, d, J=15.5 Hz), 5.87 (1H, br m), 4.59 (2H, d, J=6 Hz),3.70-3.77 (4H, m), 3.68 (3H, s), 1.72-1.80 (4H, m); MS (M+H)⁺ =357,(M+NH₄)⁺ =374. Analysis calc'd for C₂₀ H₂₄ N₂ O_(4:) C, 67.40; H, 6.79;N, 7.86; Found: C, 67.13; H, 6.62; N, 7.71.

EXAMPLE 22 Preparation of4-methoxy-4-[3-((2-(pyrid-2-yl)ethynyl)methoxy)-trans-propen-1-yl]tetrahydropyranStep 1: 4-methoxy-4-(3-methanesulfonyl-trans-prop-1-enyl)tetrahydropyran

4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran (172 mg, 1.0mmol), prepared as in Example 3, was converted to the desired compoundaccording to the method of Example 19, step 1.

Step 2:4-methoxy-4-[3-((2-(pyrid-2-yl)alkynyl)methoxy)-trans-propene1-yl]tetrahydropyran

To a stirred solution of sodium hydride (45 mg, 80% dispersion inmineral oil, 1.5 mmol) in dry THF (2 mL) was added3-(pyrid-2-yl)prop-2-ynol (133 mg, 1.00 mmol) in dry THF (1 mL). Aftergas evolution ceased, the mesylate from step 1 was added in dry THF (1mL) and the resulting mixture was stirred 17 hours at ambienttemperature. The reaction was quenched by careful addition of water andpartitioned between ethyl acetate and brine. The organic layer was dried(MgSO₄), filtered, and concentrated in vacuo. Purification bychromatography on silica gel (12 g, 25% ethyl acetate: hexanes),provided the desired compound (70 mg, 24%) as a colorless oil. ¹ H NMR(300 MHz, CDCl₃); 8.58 (1H, br d, J=4.5 Hz), 7.67 (1H, dt, J=2,8,8 Hz),7.46 (1H, d, J=8 Hz), ca 7.25 (1H, m), 5.75 (1H,br t, J=15.5 Hz), 5.67(1H, d, J=15.5 Hz), 4.42 (2H, s), 4.21 (2H, d, J=4.5 Hz), 3.65-3.80 (4H,m), 3.16 (3H, s), 1.72-1.80 (4H, m); MS (M+H)⁺ =288. Analysis calc'd forC₁₇ H₂₁ NO₃ : C, 71.06; H, 7.37; N, 4.87. Found: C, 70.86; H, 7.14; N,4.58.

The compounds represented in Table 3 are prepared by alkylation of theappropriate allylic alcohol, obtained as described in Examples 3 or 7with the requisite 3-heteroaryl-prop-2-yn-yl halide which was preparedas described in the patent literature (EP-385-663, Crawley, G. C.),according to the method of Example 1, step 4.

                  TABLE 3                                                         ______________________________________                                        Novel Aryl- and Heteroarylacetylene Substituted Olefin Triethers               ##STR13##                                                                    (Ar is as defined above)                                                      Example        R.sub.2   Ar                                                   ______________________________________                                        23             H                                                              2-pyridyl                                                                     24             Me                                                             2-pyridyl                                                                     25             H                                                              3-pyridyl                                                                     26             Me                                                             3-pyridyl                                                                     27             H                                                              4-pyridyl                                                                     28             Me                                                             4-pyridyl                                                                     29             H                                                              2-furyl                                                                       30             Me                                                             2-furyl                                                                       31             H                                                              3-furyl                                                                       32             Me                                                             3-furyl                                                                       33             H                                                              2-thienyl                                                                     34             Me                                                             2-thienyl                                                                     35             H                                                              3-thienyl                                                                     36             Me                                                             3-thienyl                                                                     37             H                                                              2-benzo[b]thienyl                                                             38             Me                                                             2-benzo[b]thienyl                                                             39             H                                                              2-benzo[b]furyl                                                               40             Me                                                             2-benzo[b]furyl                                                               41             H                                                              2-thiazoyl                                                                    42             Me                                                             2-thiazoyl                                                                    43             H                                                              2-imidazoyl                                                                   44             Me                                                             2-imidazoyl                                                                   45             H                                                              2-pyrimidyl                                                                   46             Me                                                             2-pyrimidyl                                                                   ______________________________________                                    

We claim:
 1. A compound having the structure ##STR14## or apharmaceutically acceptable salt thereof wherein Ar is selected from thegroup consisting of(a) carbocyclic aryl, optionally substituted withalkyl of from one to six carbon atoms, haloalkyl of from one to sixcarbon atoms, alkoxy of from one to six carbon atoms, or halogen; A₁ isselected from the group consisting of propynyl, methylene, and a valencebond; X is selected from the group consisting of oxygen, sulfur,sulfonyl, and NR₄, where R₄ is as defined below; and A₂ is selected fromthe group consisting of ##STR15## wherein R₃ and R₄ are independentlyhydrogen or alkyl of from one to four carbon atoms; Y is hydrogen,halogen, or nitrile, and Z is hydrogen or alkyl of from one to fourcarbon atoms, with the proviso that when X is NH, A₂ is ##STR16## R₁ isalkyl of from one to four carbon atoms; and R₂ is hydrogen or alkyl offrom one to four carbon atoms.
 2. A compound or pharmaceuticallyacceptable salt thereof as defined in claim 1 wherein A₂ is ##STR17##where R₃ is defined therein.
 3. A compound or pharmaceuticallyacceptable salt thereof as defined in claim 1 wherein A₂ is ##STR18##where R₃, Y and Z are as defined therein.
 4. A compound orpharmaceutically acceptable salt thereof as defined in claim 1 whereinA₂ is ##STR19## and X is NR₄ where X, Y, Z and R₄ are as definedtherein.
 5. A compound or pharmaceutically acceptable salt thereof asdefined in claim 1 wherein A₂ is ##STR20## and R₃ is as defined therein.6. A compound or pharmaceutically acceptable salt thereof selected fromthe group consistingof4-methoxy-4-(3-((napth-2-yl)methoxy-prop-1-ynyl)tetrahydropyran,4-methoxy-4-(3-methyl-3-(((napth-2yl)methoxy))-prop-1-ynyl)tetrahydropyran,4-methoxy-4-(3-((napth-2yl)methoxy)-trans-prop-1-enyl)tetrahydropyran,4-methoxy-4-(3-methyl-3-((napth-2yl)methoxy)-trans-prop-1-enyl)tetrahydropyran,4-methoxy-4-(3-((napth-2yl)methoxy)-prop-1-yl)tetrahydropyran,4-methoxy-4-(3-((4-phenylphen-1-yl)methoxy)-trans-prop-1-enyl)tetrahydropyran,and 4-methoxy-4-(3-(napth-2-ylthioxy)-trans-prop-1-enyl)tetrahydropyran.7. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound as defined by claim 1 in combination with apharmaceutically acceptable carrier.
 8. A method of inhibiting5-lipoxygenase enzyme activity in a mammal in need of such treatmentcomprising administering an effective amount of a compound as defined byclaim 1.